Search

Background It is reported interleukin (IL)-17A, a classical proinflammatory cytokine, is implicated in neuroimmune-associated remodeling in neural plasticity and pathological conditions. However, the effect of IL-17A on left stellate ganglion (LSG) remodeling remains unclear. Objective This study was performed to determine whether exogenous IL-17A promotes LSG remodeling and destabilize ventricular electrophysiological properties (EPs) in normal canines. Methods 24 beagles were randomly allocated into three groups. In the first group, animals were subjected to 0.1 ml phosphate buffer saline (PBS) microinjection of into LSG (n = 8), an equivalent IL-17A was administrated in the second group (n = 8), and an equivalent anti-IL-17A mAb plus IL-17A was administrated in the third group (n = 8). The ventricular EPs, neural function and activity of the LSG were determined at baseline and 30 min after administration. In the end, LSG tissues were collected. Results Compared with the control group, the experimental group had a significantly shorter effective refractory period (ERP) and action potential duration (APD)90, an increased ERP, APD90, Smax dispersion, and APD alternans cycle length; and steepened APD restitution curves. In addition, IL-17A enhanced the neural function and activity of the LSG, upregulated the expressions of neuropeptides and proinflammatory cytokines and cells. And all these effects were attenuated by anti-IL-17A mAb. Importantly, IL-17 receptor A (IL-17R-A) was detected in sympathetic neurons in the LSG. Conclusion IL-17A promoted LSG remodeling by regulating the neural inflammation response. It did so by binding to IL-17R-A, resulting in unstable ventricular electrophysiology in normal structural hearts.

Background Previous studies indicated that inhibiting the cardiac autonomic nervous system (CANS) suppressed atrial fibrillation (AF). Clinical research revealed serum adiponectin (APN) exerted a beneficial influence on sympathetic and vagal tone in patients with type 2 diabetes. However, the effects of APN on CANS is unknown. This study aims to investigate whether APN could regulate CANS and suppress rapid atrial pacing (RAP)-induced AF. Methods Eighteen beagles were divided into the control group (saline plus sham RAP, N = 6), the RAP group (saline plus RAP, N = 6) and the APN + RAP group (APN plus RAP, N = 6). APN (10 μg, 0.1 μg/μL) or saline was microinjected into 4 major ganglionated plexi (GP) prior to RAP. Atrial electrophysiological parameters, anterior right GP (ARGP) function, neural activity and GP tissues were detected. Results Compared with the control treatment, RAP shortened effective refractory period (ERP) values at all sites and increased cumulative window of vulnerability (ΣWOV), ARGP function and neural activity, whereas APN injection reversed these changes. Mechanistically, APN ameliorated RAP-induced inflammatory response and down-regulated the expression of c-fos protein and nerve growth factor. Moreover, the APN receptors 1 and APN receptors 2 were detected both in neurons and in non-neuronal cells. APN pretreatment activated downstream adenosine monophosphate-activated protein kinase (AMPK) signaling, inhibited nuclear factor-kappa B signaling and promoted macrophage phenotype switching from proinflammatory to anti-inflammatory state. Conclusions This study demonstrates that administration of APN into GP can suppress RAP-induced AF by regulating the CANS. APN signaling may provide a potential therapeutic target to AF.

Background Increased inflammation was found in the left stellate ganglion (LSG) in patients with malignant ventricular arrhythmia (VA). However, the role of inflammation in LSG remodeling is unknown. This study aimed to investigate whether exogenous interleukin-1β (IL-1β) could aggravate VA through regulating LSG remodeling. Methods Twenty-four canines who received saline (Control, n=8), IL-1β injection into the LSG (n=8) or IL-1 receptor antagonist (IL-Ra) pre-injection plus IL-1β injection (n=8) were included. Ventricular electrophysiology parameters, heart rate variability (HRV), LSG activity were measured at different time points. VA was recorded for 60min after ischemia and then LSG tissues were collected for molecular detection. Results Compared with the control group, IL-1β injection decreased the effective refractory period, action potential duration (APD) 90 and increased the maximal slope of the restitution curve in normal hearts. Besides, the occurrence of VA was significantly increased in the IL-1β group. Additionally, IL-1β injection increased the sympathetic indices of HRV and LSG activity in normal and ischemic hearts. Mechanically, the mRNA expression of pro-inflammatory cytokines and protein expression of c-fos, nerve growth factor and neuropeptide Y in LSG were increased, whereas the expression of neuronal nitric oxide synthase was decreased in the IL-1β group. More importantly, all these effects induced by IL-1β were attenuated by IL-1Ra pre-injection. Conclusion Increased inflammation induced by IL-1β injection aggravates ischemia induced VA through regulating the neuronal remodeling of the LSG. Inflammation induced neuroplasticity may be a novel mechanism and therapeutic target for VA.

Background Emerging evidence indicates gut microbes and their products could activate the autonomic nervous system (ANS), which plays important roles in the initiation and maintenance of atrial fibrillation (AF). Trimethylamine N-oxide (TMAO), a metabolite derived from gut microbes, is associated with cardiovascular diseases. The present study aimed to investigate the role of TMAO in the progression of AF. Methods In part 1: TMAO or saline was locally injected into 4 major atrial ganglionated plexi (GP) to clarify its effect on cardiac ANS and AF inducibility in normal canines. In part 2: TMAO or saline was injected into 4 major atrial GP to test its effect on AF progression in a rapid atrial pacing (RAP)-induced AF model. Results In part 1: Local injection of TMAO significantly increased anterior right GP (ARGP) function and neural activity, shortened ERP values. In part 2, compared with the control group, 6-hour RAP significantly shortened the ERP, widened the ∑WOV, enhanced the ARGP function and neural activity, increased the NGF and c-fos expression, and up-regulated the inflammatory cytokines. TMAO aggravated all of these changes by activating the proinflammatory p65 NF-κB signaling pathway. Conclusions TMAO could increase the instability of atrial electrophysiology in normal canines and aggravate the acute electrical remodeling in a RAP-induced AF model by exacerbating autonomic remodeling. The increased inflammatory cytokines in the GP due to the activation of p65 NF-κB signaling may contribute to these effects.

1. Autonomic nervous system and arrhythmiasThe autonomic nervous system plays an important role in the mod-ulation of cardiac arrhythmogenesis, and autonomic nerve activity canact as a direct trigger of arrhythmias. In atrial fibrillation, sympatheticleft stellate ganglion (LSG) and atrial ganglionated plexus activations(GP) are the most common trigger [1].2. Anti-atrial fibrillation effects induced by low-level vagus nervestimulation (LL-VNS)Inpreviousstudies,wefoundthatlow-levelvagusnervestimulation(LL-VNS), at voltages substantially below that which slowed the sinusrate significantly increases the effective refractory period (ERP) in theatria as well as the pulmonary vein (PV) myocardium. Furthermore,AFinducibilityatthesesiteswassignificantlysuppressedandtheAFdu-rationwassubstantiallyshortenedaswell.Directneuralrecordingsalsoindicatethattheanti-arrhythmiceffectsofLL-VNSaremediatedbysup-pressingtheactivityofGP[2–5].Shenetal.alsodemonstratedthatcon-tinuous LL-VNS suppressed paroxysmal atrial tachyarrhythmias inambulatory, conscious dogs via the reduction of stellate ganglionnerve activity. Histologically, LL-VNS resulted in a significant reductionof sympathetic ganglion cells in the LSG [1].3. Beneficial effects of non-invasive LL-VNSOur recent study reported a noninvasive anti-arrhythmic ap-proach to deliver VNS by transcutaneous stimulation at the tragus,where the auricular branch of the vagus nerve is located. Non-invasive LL-VNS can reverse RAP-induced atrial remodeling and in-hibit AF inducibility, suggesting a potential non-invasive treatmentfor AF [6,7].Vagus nerve stimulation (VNS) is currently used to treat refractoryepilepsy and is being investigated as a potential therapy for a range ofconditions, includingventricularfibrillation,heart failure, tinnitus,obe-sity and Alzheimer's disease. However, the invasive nature (the VNSneurostimulator system has to be implanted by surgery and maycause some side effects, such as neck pain, coughing, swallowing diffi-culty, and voice alteration along with nausea and indigestion) and ex-pense limit the use of VNS in patient populations [8–11].Although, multiple experiment and clinical studies demonstratedthat ablation of targeted neural elements reduced the incidences of ar-rhythmias. Ablation approach has also multiple limitations. One limita-tionisthattheautonomicnervoussystemishighlyplastic.It ispossiblethat reinnervation can occur after the ablation procedures and negatetheeffectsofablation.Asecondlimitationisthattheatrialganglionatedplexusand stellateganglionare noteasily accessiblein humans. Athirdlimitation is that ablation of the ganglion causes irreversible changes oftheautonomicnervoussystem.Thelong-termeffectsofautonomicner-vous system denervation in patients with arrthymia are still unknown.Because of the above limitations, it is highly desirable to develop aneuromodulation method that can be easily terminated, without caus-ing permanent damage to the autonomic structures.We examined the effects of a noninvasive therapeutic modality tosubstitute for vagus nerve stimulation. We therefore propose a newneural interface approach to optimize cardiac autonomic tone. Thesedistinguishing features that underlie the potential clinical significanceof this therapeutic approach provide us a novel, noninvasive approachto treat arrhythmias. Notably, non-invasive LL-VNS exerted powerfulanti-arrhythmiceffectswhendeliveredtoeachanimalatasubstantiallylow voltage (80% below the threshold of slowing sinus rate). This ap-proach is potentially tolerable by ambulatory patients. A very recentclinical study alsoshowed that non-invasive LL-VNS in healthyhumansreduced sympathetic nerve activity [12]. Non-invasive LL-VNS cantherefore influence human physiology and provide a simple and inex-pensive alternative to invasive VNS.